The present invention is generally related to amine oxide compounds and more particularly to amine oxide compounds and pharmaceutically acceptable salts that are antagonists of the of the Neurokinin 1 (NK-1, substance P) receptor which are prodrugs for delivery of known compounds with antagonistic activity to the Neurokinin 1 (NK-1, substance P) receptor.
A prodrug is in most cases a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. It has been shown that a molecule with optimal structural configuration and physicochemical properties for eliciting the desired therapeutic response at its target site does not necessarily possess the best molecular form and properties for its delivery to its point of ultimate action. Usually, only a minor fraction of doses administered reach the target area and since most agents interact with non-target sites as well, an inefficient delivery may result in undesirable side effects. This fact of differences in transport and in situ effect characteristics for many drug molecules is the basic reason why bioreversible chemical derivatization of drugs, i.e., prodrug formation is a means by which a substantial improvement in the overall efficacy of drugs can often be achieved. Prodrugs are designed to overcome pharmaceutically and/or pharmacokinetically based problems associated with the parent drug molecule that would otherwise limit the clinical usefulness of the drug.
In recent years several types of bioreversible derivatives have been exploited for utilization in designing prodrugs. Using esters as a prodrug type for drugs containing carboxyl or hydroxyl function is most popular. Further well-known are prodrug derivatives of peptides, 4-imidazolidinones and the like, described in Drugs of the Future, 1991, 16(5), 443-458 or N-oxides, described for example in U.S. Pat. No. 5,691,336.
The compounds of formula II 
are antagonists of the neurokinin receptor. The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993 reviews the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyper-reactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 describes the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Further, the usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is described in Neuropeptides, 32(1), 1-49, (1998) and Eur. J. Pharmacol., 383(3), 297-303, (1999).
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
The present invention relates to N-oxides of compounds of the formula 
wherein
R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R1 is hydrogen or halogen; or, when n=1, R and R1, when adjacent, together can additionally bridge between the ring carbon atoms to which they are attached to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
R2 and R2xe2x80x2 are hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; or
R2 and R2xe2x80x2 when adjacent, and when n=1, together can additionally bridge between the ring carbon atoms to which they are attached to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 unsubstituted or substituted by one or two lower alkyl or lower alkoxy;
R3, R3xe2x80x2 are hydrogen, lower alkyl or cycloalkyl;
R4, R4xe2x80x2 are xe2x80x94(CH2)mOR6 or lower alkyl; or
R4 and R4xe2x80x2 together with the N-atom to which they are attached form a 5 or 6 member nitrogen containing heterocyclic ring of the structure 
xe2x80x83wherein said heterocyclic ring has 0 or 1 additional hetero-atoms selected the group consisting of sulfur, nitrogen and oxygen, said additional hetero-sulfur atom being a sulfide, sulfone, or sulfonyl moiety;
R5 is hydrogen, hydroxy, lower alkyl, -lower alkoxy, xe2x80x94(CH2)mOH, xe2x80x94COOR3, xe2x80x94CON(R3)2, xe2x80x94N(R3)CO-lower alkyl or xe2x80x94C(O)R3;
R6 is hydrogen, lower alkyl or phenyl;
X is xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94N(R6)C(O)xe2x80x94, xe2x80x94(CH2)mOxe2x80x94 or xe2x80x94O(CH2)mxe2x80x94;
n is 0, 1, 2, 3 or 4; and
m is 1, 2 or 3;
and to pharmaceutically acceptable acid addition salts thereof.
It has surprisingly been found that these N-oxides of the present invention have an in vitro activity on the NK1 receptor and/or may be used as prodrugs of compounds of formula 
which are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
However, the advantage of a prodrug lies in its physical properties, such as enhanced water solubility for parenteral administration compared to the parent drug, or it enhances absorption from the digestive tract, or it may enhance drug stability for long-term storage. Compounds of formula II have limited water solubility, not allowing bolus injections. It was therefore useful to find derivatives of the compound of formula II to render these compounds suitable for parenteral and intramuscular application. It has been shown that N-oxides of compounds of formula I fulfill all requirements of a good prodrug.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
The most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group, containing 3-6 carbon atoms.
The term xe2x80x9c5 or 6 member nitrogen containing heterocyclic ring of the structure 
having 0 or 1 additional hetero-atoms selected from sulfur, nitrogen and oxygen, and the additional hetero-sulfur atom being a sulfonyl moiety;xe2x80x9d denotes, for example, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl, and the like.
A preferred compound of the invention of structure I includes the compound of structure 
wherein R, R3, R3xe2x80x2 and R2 and R2xe2x80x2 are as defined above.
Preferred compounds are those, wherein R is methyl or chloro, for example the following compounds:
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-oxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-oxy-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-oxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-acetamide,
2-(3,5-dimethoxy-phenyl)-N-methyl-N-[6-(4-oxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-acetamide, or
2-(3fluoro-5-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-oxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-acetamide.
Further preferred are compounds of claim 1 having the structure 
wherein R, R2 and R2xe2x80x2, and R3 and R3xe2x80x2 and n are as defined above, for example the following:
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-oxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide.
Preferred are further compounds of claim 1 having the structure 
wherein R, R2 and R2xe2x80x2, and R3 and R3xe2x80x2 and n are as defined above.
A preferred embodiment of compounds of formula Ic are those, wherein R is methyl, for example the followings:
N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide,
N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide,
N-methyl-6-(4-oxy-morpholin-4-yl)-N-naphthalen-1-ylmethyl-4-o-tolyl-nicotinamide,
N-(2-methoxy-naphthalen-1-ylmethyl)-N-methyl-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide,
N-(2-methoxy-benzyl)-N-methyl-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide,
N-(5-chloro-2-methoxy-benzyl)-N-methyl-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide,
N-(2-chloro-5-methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide,
N-methyl-6-(4-oxy-morpholin-4-yl)-N-pentafluorophenylmethyl-4-o-tolyl-nicotinamide,
N-methyl-6-(4-oxy-morpholin-4-yl)-N-naphthalen-2-ylmethyl-4-o-tolyl-nicotinamide,
N-[2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-N-methyl-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide or
N-(1,4-dimethoxy-naphthalen-2-ylmethyl)-N-methyl-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide.
Preferred are further compounds having the structure 
wherein R, R2 and R2xe2x80x2, R3 and R3xe2x80x2 and R4 and R4xe2x80x2 and n are as defined in claim 1.
Compounds of formula Id, wherein R is chloro, are especially preferred, for example the following compounds:
2-(3,5-bis-trifluoromethyl-phenyl)-N-[4xe2x80x2-(2-chloro-phenyl)-1-oxy-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-5xe2x80x2-yl]-N-methyl-isobutyramide or
2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-oxy-dimethylamino-pyridin-3-yl]-isobutyramide.
The compounds of formula Id, wherein R is methyl, are also preferred. Such compounds are:
2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-oxy-dimethylamino-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-1-(4-hydroxy-1-oxy-4xe2x80x2-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-5xe2x80x2-yl)-N-methyl-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-{6-[(2-hydroxy-ethyl)-1-oxy-methyl-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide or
(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-1-oxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.
The compounds having the structure 
are also preferred, wherein R, R2, R2xe2x80x2, R3, R3xe2x80x2 and R4 and R4xe2x80x2 and n are as defined above.
Examples of compounds of formula Ie, wherein R is methyl, are the followings:
4-{5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-4-oxy-piperazine-1-carboxylic acid tert-butyl ester,
5xe2x80x2-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4xe2x80x2-o-tolyl-1-oxy-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-4-carboxylic acid ethyl ester,
(RS)-6-[3-(acetyl-methyl-amino)-1-oxo-pyrrolidin-1-yl]-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-bis-trifluoromethyl-benzyl)-6-(1,1-dioxo-1xcex6-4-oxy-thiomorpholin-4-yl)-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-bis-trifluoromethyl-benzyl)-6-(4-formyl-1-oxy-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide or
5xe2x80x2-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4xe2x80x2-o-tolyl-1-oxy-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-4-carboxylic acid.
Examples of compounds of formuls I, further comprising R2, R2xe2x80x2 being adjacent and taken together with the ring carbons to which they are attached to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, are the followings:
N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide,
N-methyl-6-(4-oxy-morpholin-4-yl)-N-naphthalen-1-ylmethyl-4-o-tolyl-nicotinamide,
N-(2-methoxy-naphthalen-1-ylmethyl)-N-methyl-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide,
N-methyl-6-(4-oxy-morpholin-4-yl)-N-naphthalen-2-ylmethyl-4-o-tolyl-nicotinamide or
N-(1,4-dimethoxy-naphthalen-2-ylmethyl)-N-methyl-6-(4-oxy-morpholin-4-yl)-4-o-tolyl-nicotinamide.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
oxidizing a compound of formula 
with a suitable oxidizing agent to give a compound of formula 
wherein the substituents have the significances given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
In accordance with this procedure, a compound of formula I may be prepared, for example, as follows: To a solution of 10 mmol of a compound of formula II in 50 ml of a suitable solvent such as dichloromethane is added under ice cooling a solution of 10 mmol of a suitable oxidizing reagent such as 3-chloroperbenzoic acid in 50 ml of a suitable solvent such as dichloromethane. Stirring is continued for an appropriate time (typically 1 h to 24 h) at 0xc2x0 C. and reaction progress may be followed by thin-layer-chromatography. In cases in which product formation is too slow, the reaction mixture may be stirred at room temperature. After evaporation of the solvent products of formula I can be isolated by flash-chromatography in 15% to 85% yield. Further purification of crystalline products may be achieved by recrystallization from a suitable solvent.
For this transformation other oxidizing reagents may be used instead of 3-chloroperbenzoic acid. Those oxidizing reagents are familiar to any person skilled in the art such as dimethyldioxirane in acetone, hydrogenperoxide in acetic acid or potassium peroxymonosulfate in a suitable solvent such as water.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1-8 describe the processes for preparation of compounds of formula I in more detail. The starting materials are known compounds and may be prepared according to methods known in the art, for example in accordance with methods, described in EP 1035115.
In the schemes the following abbreviations have been used:
PivCl pivaloyl chloride
THF tetrahydrofuran
TMEDA N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylene diamine
DIPEA N-ethyldiisopropyl-amine
KHMDS potassium hexamethyldisilazide 
The definition of substituents is given above. 
The definition of substituents is given above. 
and the definition of the other substituents is given above. 
The definition of substituents is given above. 
Z is Cl, Br, I or xe2x80x94OS(O)2C6H4CH3 and the definition of the other substituents is described above. 
Z is Cl, Br, I or xe2x80x94OS(O)2C6H4CH3 and the definition of the other substituents is given above. 
R5xe2x80x2 is the group xe2x80x94C(O)R3 and the definition of the remaining substituents is given above. 
The definition of substituents is given above.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts may be used as prodrugs of the parent compounds of formula II, which possess valuable pharmacological properties. These compounds are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
Furthermore, in addition, some N-oxides of formula I have a good affinity to the NK1 receptor. For some preferred compounds the pKi value is in the range of 8.3 to 8.7.
All of the preferred compounds of the invention were investigated in accordance with the tests given hereinafter.
Binding Assay (In Vitro)
The affinity of test compounds for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The evidence, that the compounds of formula I may be used as prodrugs of their parent compounds of formula II is shown in accordance with the description given hereinafter.
The conversion of N-oxide prodrugs to the corresponding parent compounds is due to a reduction mechanism. There is some evidence from the literature that similar reactions occur in vivo and are probably catalysed by hemoglobin, hence the decision to study both the stability in plasma and blood was taken. The presence of an oxidant in the work-up solution should help preventing the reduction of the N-oxides.
Conversion in plasma: 10 xcexcLs of a 100 xcexcg/mL DMSO solution of the pro-drug were added to 1 mL plasma to reach a final concentration of 1 xcexcg/mL. The incubation was performed at 37xc2x0 C. and 8 aliquots were taken at different time points over 30 min. These aliquots were treated with 3 volumes of cold MeOH containing H2O2 (final concentration 10% v/v) and centrifuged at 3500 g for 20 min at 10xc2x0 C. The supernatant was directly used to determine the drug levels by LC-MS-MS (HPLC chromatography on reversed phase column X-Terra MS C18 3.5 xcexcM 2.1xc3x9730 mm Waters at 40xc2x0 C., using a polarity gradient MeOH/Form.Ac. 1% 20/80/MeOH; run time; 3.0 min; inj. Vol.: 10 xcexcL; Flow: 0.2 xcexcL/min and MS/MS detection on a PE Sciex API-2000 MS/MS spectrometer; ion source: Turbospray; ionisation mode: ESP+).
Conversion in fresh blood: The same procedure was used for the stability studies in blood, even if much more care had to be taken after treatment with the H2O2.
Sample stability (plasma and blood): The final matrix were first prepared (plasma or blood treated with 3 volumes of cold MeOH containing H2O2xe2x80x9410% v/vxe2x80x94and centrifuged at 3500 g for 20 min at 10xc2x0 C.) and then incubated at 37xc2x0 C. into two tubes; the pro-drug or the drug were then incubated and finally their concentration determined by LC-MS-MS as described above.
The method used to stop the reaction in both plasma and blood was found to be enough reliable to perform the studies at least when the analysis was performed immediately after the incubations.
The half-life obtained for the conversion prodrug to drug in plasma are reported in the following table (Plasma sample preparation was found to be critical for exact determination of values for t1/2):
The stability in blood is much lower (t1/2 less than 30 min) and it was impossible to determine a precise value of t1/2. However we can conclude that there are no major species difference with respect with stability in blood and that the prodrugs are converted to the desired drugs in high yield. ( greater than 90%).
In accordance with the tests the compounds of formula I can function as prodrugs of their parent compounds of formula II.
The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragxc3xa9es and hard gelatine capsules.
Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
The following preferred examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.
The preparation of compounds of formula I, starting with compounds of formula II, is described generically in the description. This oxidation procedure is always the last step to obtain the N-oxides of compounds of formula I. A detailed description of this last step is specifically described in the following examples 1, 2 and 13. The N-oxidation of the remaining compounds 3 to 12 and 14 to 29 is generically described in accordance with the above mentioned description.